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54 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 55

(CD150+, CD244−, CD48−). Nearly half of the individual cells in the erythroid hematopoietic cells that populate the logettes are derived not
CD150+, CD244−, CD48− population provide long-term hematopoi- from HSCs but rather from later-committed progenitors. Just after
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etic reconstitution in irradiated mice. 52 birth the HSCs are found in the marrow, and hematopoiesis is evident
Derivation of hematopoietic cells from adult tissue (muscle, liver) throughout the marrow cavity.
is attributed to resident marrow-derived stem cells in these tissues. 54,55
A role for adult marrow-derived mesenchymal stem cells in the repair Adipose Tissue
and regeneration of nonmarrow organs has been described, includ- By the fourth year of life, a significant number of fat cells have appeared
ing cardiac and smooth muscle, liver, and brain. 56,57 However, these in the diaphysis of the human long bones. These cells slowly replace
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marrow-derived mesenchymal stem cells function mainly by providing hematopoietic elements and expand centripetally until, at approx-
a microenvironment through various cytokines that induce cell growth imately 18 years of age, hematopoietic marrow is found only in the
and stimulate vascularization or by fusing with local cells, rather than by vertebrae, ribs, skull, pelvis, and proximal epiphyses of the femora and
transdifferentiation into specific differentiated cells of the organ under- humeri. Direct measurements of the volume of bone cavities reveal
going repair (Chap. 18). 56,57 increases from 1.4 percent of body weight at birth to 4.8 percent in the
adult, whereas blood volume decreases from 8 percent of body weight
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in the newborn to approximately 7 percent in the adult. Expansion of
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HISTOGENESIS marrow space continues throughout life, resulting in a further gradual
Stroma and Hematopoietic Tissue increase in the amount of fatty tissue in all bone cavities, especially in
The formation of the marrow in the third trimester of mammalian pre- the long bones. 68,69 Although the quantity of adipose tissue in the head
natal development involves the circulation and chemotaxis of HSCs, and trochanteric parts of the femur varies in individuals, the fat con-
which have greatly expanded their numbers in the fetal liver, to the tent of this area of hematopoietic marrow progressively increases as
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newly developed marrow niche (see “Marrow Structure” below). The adult humans age. The preference of hematopoietic tissue for centrally
release of HSC from the murine fetal liver coincides with the progres- located bones has been ascribed to higher central tissue temperature
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sive loss of two adhesion proteins, CD144 (VE-cadherin) and CD41 with greater vascularity. In mice, an increased prevalence of adipose
(integrin α ). 58,59 In mice, the seeding of the marrow with HSCs is first tissue in tail vertebrae as opposed to the more central thoracic vertebrae
2b
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detected at 17.5 dpc, but the formation of the marrow niches for the is associated with fewer HSCs and hematopoietic progenitors. Genetic
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HSCs and their progeny occurs in the preceding 3 days in sites of endo- absence of adipose tissue or chemical inhibition of adipocyte generation
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chondral bone formation. Differentiation of a clonal skeletal progen- was associated with improved posttransplant hematopoietic regenera-
itor stem cell results in cell populations that form cartilage, bone, or tion, suggesting that marrow adipocytes are negative regulators in the
marrow niches that either support HSCs or the differentiating prog- hematopoietic microenvironment. 72
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eny of HSCs. The specific cells supported by a niche depend upon
the expressions of endoglin, Thy1, and aminopeptidase A by the mes-
enchymal descendants of the skeletal progenitor stem cell. The migra- MARROW STRUCTURE
tion of the circulating HSCs to their supporting marrow niches, which
are formed by cells expressing aminopeptidase A but not endoglin or VASCULATURE
Thy1, is directed by the synergistic action of the chemokines CXCL12 The blood supply to the marrow comes from two major sources. The
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and SCF for which the HSCs display the respective receptors, CXCR4 nutrient artery, the principal source, penetrates the cortex through the
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and KIT. Other chemotactic factors and adhesion molecules contrib- nutrient canal. In the marrow cavity, the nutrient artery bifurcates into
ute to HSC migration from the fetal liver to the developing bone where ascending and descending central or medullary arteries from which
their seeding and differentiation initiates marrow hematopoietic func- radial branches travel to the inner face of the cortex. After repenetrating
tion in mammals. 58–60 the endosteum, the radial vessels diminish in caliber to structures of
Cavities within bone occur in the human being at about the fifth capillary size that course within the canalicular system of the cortex.
fetal month and soon become the exclusive site for granulocytic and In the canalicular system, arterial blood from the nutrient artery mixes
megakaryocytic proliferation. Erythropoietic activity at the time is con- with blood that enters the cortical capillary system from the periosteal
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fined to the liver. The microenvironment in the marrow becomes sup- capillaries derived from muscular arteries. After reentering the mar-
portive of erythroblasts only toward the end of the last trimester (see row cavity, the cortical capillaries form a sinusoidal network (Fig. 5–2).
Fig. 5–1). The formation of the marrow cavities in the developing mouse Hematopoietic cells are located in the intersinusoidal tissue spaces.
bones appear at a relatively later time in the prenatal life of mice than Some arteries have specialized, thin-walled segments that arise abruptly
humans, and it involves an IHH-regulated synchronized maturation of as continuations of arteries with walls of normal thickness. These
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osteoblast progenitors arising from mesenchymal stem cells and osteo- vessels give off nearly perpendicular branches analogous to the arte-
clast progenitors arising from HSCs in the areas of mineralized cartilage rial branching observed in the spleen and kidney, permitting volume
of the fetal bones. Most of the marrow spaces form in the endochon- compensation for changes in intramedullary pressure. In the marrow
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dral bones but some marrow develops in the intramembranous bones cavity, blood flows through a highly branching network of medullary
of the cranium and scapulae. As these respective progenitors differ- sinuses. These sinuses collect into a large central sinus from which the
entiate in situ they acquire the phenotype of osteoblasts with expres- blood enters the systemic venous circulation through emissary veins.
sion of osteopontin, osteonectin, bone sialoprotein, and macrophage Histomorphic studies of normal murine marrow demonstrate that all
colony-stimulating factor (M-CSF), and of osteoclasts with expression hematopoietic cells are within 18 μm or less than 3 cell diameters of a
of tartrate-resistant acid phosphatase (TRAP), calcitonin receptors, blood vessel. 75
and c-FMS (M-CSF receptor). In the human, marrow hematopoiesis Vascular networks consisting of cells expressing CD31, CD34,
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begins at the 11th week of gestation in specialized mesodermal struc- and CD105 (endoglin) but lacking intercellular adhesion molecule
tures termed primary logettes. The logettes are composed of mesenchy- (ICAM)-1, ICAM-2, ICAM-3, or endothelial leukocyte adhesion mol-
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mal cells and fibers that surround a central artery and protrude into ecule (ELAM)-1 (E-selectin) can form within the stroma of long-term
the venous sinuses of the developing marrow cavities. The myeloid and marrow cultures. These findings underscore the intimate relationship of

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